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LncRNA GAL promotes colorectal cancer liver metastasis through stabilizing GLUT1

Oncogene volume 41, pages 1882–1894 (2022)Cite this article

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Abstract

Colorectal cancer liver metastasis (CRLM) is the leading cause of colorectal cancer-related deaths and remains a clinical challenge. Enhancement of glucose uptake is involved in CRLM; however, whether long noncoding RNAs (lncRNAs) participate in these molecular events remains largely unclear. Here, we report an lncRNA, GAL (glucose transporter 1 (GLUT1) associated lncRNA), that was upregulated in CRLM tissues compared with primary colorectal cancer (CRC) tissues or matched normal tissues and was associated with the overall survival rates of CRLM patients. Functionally, GAL served as an oncogene because it promoted CRC cell migration and invasion in vitro and enhanced the ability of CRC cells to metastasize from the intestine to the liver in vivo. Mechanistically, GAL interacted with the GLUT1 protein to increase GLUT1 SUMOylation, inhibiting the effect of the ubiquitin-proteasome system on the GLUT1 protein. GLUT1-knockout (−/+) repressed the GAL-mediated increase in CRC cell uptake of glucose, migrate, and invade in vitro, as well as metastasis from the intestine to the liver in vivo, and enforced expression of GLUT1 rescued GAL knockout-induced biological functions in CRC cells. Taken together, our findings demonstrated that GAL promotes CRLM by stabilizing GLUT1, suggesting that the GAL-GLUT1 complex may act as a potential therapeutic target for CRLM.

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Fig. 1: Global analyses of lncRNAs associated with glucose metabolism in CRLM.
Fig. 2: GAL promotes CRC cell metastasis in vitro and in vivo.
Fig. 3: 101-217 nt of GAL interacts with GLUT1 protein in CRC cells.
Fig. 4: GAL stabilizes GLUT1 protein by enhancing its SUMOylation in CRC cells.
Fig. 5: The GAL-GLUT1 complex regulates glucose uptake in vitro and CRLM in vivo.
Fig. 6: The high levels of GAL and GLUT1 proteins are associated with the poor survival rates of patients with CRLM.
Fig. 7: A schematic diagram reveals the regulatory mechanism by which GAL stabilizes GLUT1 protein.

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Data availability

sgRNA Designer is available in the website (https://portals.broadinstitute.org/gpp/public/analysis-tools/sgrna-design).

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Funding

This work was supported by grants from the Natural Science Foundation of China (81773037) and the Chongqing Science and Technology Commission Fund (cstc2019jcyj-msxmX0378 and cstc2019jcyj-bshX0040).

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Author notes

  1. These authors contributed equally: Bosheng Li, Houyi Kang, Yufeng Xiao.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China

    Bosheng Li, Yan Zhang, Fan Yang & Fengtian He

  2. Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China

    Bosheng Li, Yufeng Xiao, Yexiang Du & Shiming Yang

  3. Department of Radiology, Daping Hospital, Army Medical University, Chongqing, 400042, China

    Houyi Kang & Yu Guo

  4. Department of Radiology, Southwest Hospital, Army Medical University, Chongqing, 400038, China

    Yunhua Xiao

  5. Department of Urology, Southwest Hospital, Army Medical University, Chongqing, 400038, China

    Guojing Song

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Contributions

BL, FH, and SY designed this study. BL and HK performed all experiments. Yufeng X and YD participated in cell culture and CRISPR/cas9-mediated gene knockout. Yunhua X, YG, and GS participated in establishing the nude mice model. YZ guided several experiments. BL and FH drafted the manuscript.

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Correspondence to Fengtian He or Shiming Yang.

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Li, B., Kang, H., Xiao, Y. et al. LncRNA GAL promotes colorectal cancer liver metastasis through stabilizing GLUT1. Oncogene 41, 1882–1894 (2022). https://doi.org/10.1038/s41388-022-02230-z

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